Sentinel lymph node localization and biopsy has become a standard of care in determining regional lymph node status and reducing operative morbidity in patients with malignant neoplasms such as melanoma and breast cancer. Sentinel node techniques include pre-operative lymphoscintigraphy in combination with intra-operative localization using perilesionally injected radiocolloid tracers and/or blue dye, handheld gamma detectors and surgical dissection. Accuracy is variable and depends on the experience of the surgeon and the specific protocol employed. Limitations include indirect localization of nodes, localization ambiguity when radiotracers distribute to more distant lymph nodes, logistical limitations imposed by coordination of nuclear medicine and surgical services and a steep learning curve for surgical proficiency. We have recently shown that contrast-assisted ultrasound (US) lymphography following subcutaneous or peritumoral injection of US contrast bubbles can be used effectively to enhance regional lymph nodes and that submicron and near micron-sized bubbles appear to be more effective than conventional intravascular microbubbles for this purpose. We therefore propose an alternative method for sentinel node detection using contrast-enhanced power Doppler US with submicron and near-micron contrast microbubbles. Advantages are that nodes and associated afferent lymphatic vessels can be visualized directly and noninvasively in real-time, logistical and radiation safety issues associated with radiocolloid use are avoided and nodes predominantly replaced by tumor may be still be detected due to the exquisite contrast resolution of contrast-enhanced power Doppler US. Specific aims of this study are 1) to acoustically and optically characterize submicron and near-micron bubble response to clinically relevant insonation as a basis for optimizing US scanning parameters; 2) characterize contrast microbubble distribution at injections sites and within targeted lymph nodes using intervital microscopy and histochemistry techniques; 3) optimize an US sentinel node detection protocol in a proven normal canine model and; 4) document sentinel node detection accuracy in a swine model of cutaneous melanoma. Successful completion of this study will lead to an alternative method for intra-operative sentinel node localization that may obviate many of the limitations of current techniques.